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Lancet (London, England) Oct 2023Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX... (Randomized Controlled Trial)
Randomized Controlled Trial
NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.
BACKGROUND
Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC).
METHODS
NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m, oxaliplatin 60 mg/m, leucovorin 400 mg/m, and fluorouracil 2400 mg/m, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m and gemcitabine 1000 mg/m, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235.
FINDINGS
Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel-gemcitabine, 387; median follow-up 16·1 months [IQR 13·4-19·1]). Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine (hazard ratio 0·83; 95% CI 0·70-0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel-gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel-gemcitabine group.
INTERPRETATION
Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC.
FUNDING
Ipsen.
TRANSLATION
For the plain language summary see Supplementary Materials section.
Topics: Humans; Gemcitabine; Paclitaxel; Pancreatic Neoplasms; Albumins; Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37708904
DOI: 10.1016/S0140-6736(23)01366-1 -
The Lancet Regional Health. Western... Nov 2023Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood...
Paclitaxel liposome, cisplatin and 5-fluorouracil-based induction chemotherapy followed by de-escalated intensity-modulated radiotherapy with concurrent cisplatin in stage IVA-IVB childhood nasopharyngeal carcinoma in endemic area: a phase II, single-arm trial.
BACKGROUND
Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation.
METHODS
We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60 Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70 Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT).
FINDINGS
From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation.
INTERPRETATION
Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients.
FUNDING
A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
PubMed: 37691885
DOI: 10.1016/j.lanwpc.2023.100895 -
Journal of the College of Physicians... Sep 2023To determine the differences in terms of overall survival in platinum-sensitive ovarian cancer (PSOC) patients undergoing various chemotherapy protocols, and to... (Observational Study)
Observational Study
OBJECTIVE
To determine the differences in terms of overall survival in platinum-sensitive ovarian cancer (PSOC) patients undergoing various chemotherapy protocols, and to demonstrate patient tolerance, toxicity, and efficacy data with the use of bevacizumab in different protocols.
STUDY DESIGN
An observational study. Place and Duration of the Study: Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey, from January 2018 to January 2022.
METHODOLOGY
Patients aged 18 and above, who had received treatment for PSOC, were included in the study. Patients with platinum-resistant disease and those for whom bevacizumab usage was contraindicated were not enrolled in the study.
RESULTS
For the 95 patients, the median age was 55 (34-78) years. Median follow-up are 39.7 (39.2-47.5) months. Median progression-free survival (PFS) of the patients are 10.8 (7.3-14.0) months for carboplatin-gemcitabine-bevacizumab (CGB), 10.9 (IQR 5.5-14.3) months in the carboplatin-liposomal doxorubicin-bevacizumab (CLdB) arms, and 6.1 (IQR 5.8-14.3) months in the carboplatin-paclitaxel-bevacizumab (CPB) group (p=0.79). The median overall survivals (OS) are 37.9 (IQR 33.3-46.9) months in the CGB arm, 41.0 (IQR 38.0-50.3) months CPB arm, and 41.3 (IQR 38.1-52.3) months in the CLdB arm (p=0.173).
CONCLUSION
There was no difference in terms of overall survival among all three chemotherapy protocols. However, due to the difference in toxicity, the treatment should be selected on a patient-specific basis. Additionally, the use of bevacizumab at a dose of 7.5 mg/kg was demonstrated to be equivalent to using 15 mg/kg in terms of overall survival. This lower dose is also important to avoid financial toxicity.
KEY WORDS
Bevacizumab, Ovarian cancer, Platinum-based chemotherapy, Tolerability, Adverse clinical events.
Topics: Humans; Female; Middle Aged; Bevacizumab; Carboplatin; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Gemcitabine
PubMed: 37691362
DOI: 10.29271/jcpsp.2023.09.1006 -
Lutein-Based pH and Photo Dual-Responsive Novel Liposomes Coated with Ce6 and PTX for Tumor Therapy.ACS Omega Aug 2023Liposomes are considered the best nanocarrier for delivering cancer drugs such as chlorin e6 (Ce6) and paclitaxel (PTX). However, the poor stability and non-selectivity...
Liposomes are considered the best nanocarrier for delivering cancer drugs such as chlorin e6 (Ce6) and paclitaxel (PTX). However, the poor stability and non-selectivity release of liposomes may severely limit their further applications. In this study, based on the characteristics of lutein (L) photo-response and orthoester (OE) acid-response, stable and dual-responsive liposomes (Dr-lips) have been prepared. The Dr-lips exhibited a spherical shape with a uniform size of approximately 58.27 nm. Moreover, they displayed a zeta potential ranging from -45.45 to -28.25 mV and showed excellent storage stability, indicating stable colloidal properties. Additionally, they achieved high drug encapsulation rates, with 92.27% for PTX and 90.34% for Ce6, respectively. Meanwhile, under near-infrared (NIR) light at 660 nm, Ce6 plays a key role in accelerating the photodegradation rate of lutein and PEG-OE-L while also enhancing tissue penetration ability. Additionally, Dr-lips loaded with Ce6 and PTX not only displayed excellent pH and photo dual-responsiveness for targeted delivering and releasing but also showed remarkable reactive oxygen species (ROS) generation capacity and impressive anti-tumor activity in vitro. Therefore, it provides a novel strategy for optimizing stability and enhancing their targeted drug delivery of liposome.
PubMed: 37663483
DOI: 10.1021/acsomega.3c04228 -
Clinical and Experimental Medicine Dec 2023To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women...
AIMS
To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months.
METHODS
The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years.
RESULTS
Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and, of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes.
CONCLUSIONS
The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.
Topics: Humans; Female; Aged; Breast Neoplasms; Stroke Volume; Ventricular Function, Left; Neoplasm Recurrence, Local; Doxorubicin; Cyclophosphamide; Polyethylene Glycols; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 37634231
DOI: 10.1007/s10238-023-01144-8 -
ACS Nano Sep 2023Paclitaxel (PTX)-based chemotherapy remains the main approach to treating lung cancer but systemic toxicity limits its use. As chimeric antigen receptor-T (CAR-T)...
Paclitaxel (PTX)-based chemotherapy remains the main approach to treating lung cancer but systemic toxicity limits its use. As chimeric antigen receptor-T (CAR-T) cell-derived exosomes contain tumor-targeted CARs and cytotoxic granules (granzyme B and perforin), they are considered potential delivery vehicles for PTX. However, the low drug-loading capacity and hepatotropic properties of exosomes are obstacles to their application to extrahepatic cancer. Here, a hybrid nanovesicle named Lip-CExo@PTX was designed for immunochemotherapy of lung cancer by fusing exosomes derived from bispecific CAR-T cells targeting both mesothelin (MSLN) and programmed death ligand-1 (PD-L1) with lung-targeted liposomes. Due to the lung-targeting ability of the liposomes, over 95% of intravenously administered Lip-CExo@PTX accumulated in lung tissue. In addition, with the help of the anti-MSLN single-chain variable fragment (scFv), the PTX and cytotoxic granules inside Lip-CExo@PTX were further delivered into MSLN-positive tumors. Notably, the anti-PD-L1 scFv on Lip-CExo@PTX blocked PD-L1 on the tumors to avoid T cell exhaustion and promoted PTX-induced immunogenic cell death. Furthermore, Lip-CExo@PTX prolonged the survival time of tumor-bearing mice in a CT-26 metastatic lung cancer model. Therefore, Lip-CExo@PTX may deliver PTX to tumor cells through sequential targeted delivery and enhance the antitumor effects, providing a promising strategy for immunochemotherapy of lung cancer.
Topics: Animals; Mice; Receptors, Chimeric Antigen; Liposomes; Exosomes; T-Lymphocytes; Lung Neoplasms; Paclitaxel
PubMed: 37624742
DOI: 10.1021/acsnano.3c03456 -
Journal of Materials Chemistry. B Sep 2023Photodynamic therapy is an effective method for the treatment of several types of cancerous and noncancerous diseases. The key to the success of this treatment method is... (Review)
Review
Photodynamic therapy is an effective method for the treatment of several types of cancerous and noncancerous diseases. The key to the success of this treatment method is effective drug delivery to the site of action, for instance, a tumor. This ensures not only the high effectiveness of the therapy but also the suppression of side effects. But how to achieve effective targeted delivery? Lately, much attention has been paid to systems based on the so-called Trojan horse model, which is gaining increasing popularity. The principle of this model is that the effective drug is hidden in the internal structure of a nanoparticle, liposome, or nanoemulsion and is released only at the site of action. In this review article, we focus on drugs from the group of mitotic poisons, taxanes, and their use with photosensitizers in combined therapy. Here, we discuss the possibilities of how to improve the paclitaxel and docetaxel bioavailability, as well as their specific targeting for use in combined photo- and chemotherapy. Moreover, we also present the state of the art multifunctional drugs based on cabazitaxel which, owing to a suitable combination with photosensitizers, can be used besides photodynamic therapy and also in photoacoustic imaging or sonodynamic therapy.
Topics: Photosensitizing Agents; Photochemotherapy; Drug Delivery Systems; Taxoids; Paclitaxel
PubMed: 37615658
DOI: 10.1039/d2tb02147a -
Journal of Liposome Research Jun 2024The object of the current study was to develop and evaluate trastuzumab-conjugated Paclitaxel (PTX) and Elacridar (ELA)-loaded PEGylated pH-sensitive liposomes (TPPLs)...
The object of the current study was to develop and evaluate trastuzumab-conjugated Paclitaxel (PTX) and Elacridar (ELA)-loaded PEGylated pH-sensitive liposomes (TPPLs) for site-specific delivery of an anticancer drug. In this study, paclitaxel is used as an anticancer drug which promotes microtubules polymerization and arrest cell cycle progression at mitosis and subsequently leading to cell death. The single use of PTX causes multiple drug resistance (MDR) and results failure of the therapy. Hence, the combination of PTX and P-glycoprotein inhibitor (ELA) are used to achieve maximum therapeutic effects of PTX. Moreover, monoclonal antibody (trastuzumab) is used as ligand for the targeting the drug bearing carriers to BC. Thus, trastuzumab anchored pH-sensitive liposomes bearing PTX and ELA were developed using thin film hydration method and Box-Behnken Design (BBD) for optimizing various formulation variables. The optimized liposomes undergo characterization such as vesicle size, PDI, and zeta potential, which were observed to be 122 ± 2.14 nm, 0.224, and -15.5 mV for PEGylated pH-sensitive liposomes (PEG-Ls) and 134 ± 1.88 nm, 0.238, and -13.98 mV for TPPLs, respectively. The results of the drug release study of both formulations (PEG-Ls and TPPLs) showed enhanced percentage drug release at an acidic pH 5 as compared to drug release at a physiological pH 7.4. Further, the cytotoxicity studies were performed in the SK-BR-3 and MDA-MB-231 cell lines. The cellular uptake study of FITC-loaded TPPLs in SK-BR-3 cells showed greater uptake than FITC-loaded PEG-Ls, while in MDA-MB-231 cells there was no significant difference in cell uptake between FITC-loaded TPPLs and FITC-loaded PEG-Ls. Hence, it can be concluded that the HER-2 overexpressing cancer cell line (SK-BR-3) was showed better cytotoxicity and cell uptake of TPPLs than the cells that expressed low levels of HER2 (MDA-MB-231). The tumor regression study, TPPLs showed significantly more tumor burden reduction i.e. up ∼74% as compared to other liposomes after 28 days. Furthermore, the studies of TPPLs showed a minimal toxicity profile, minimal hemolysis, higher tumor tissue distribution, and superior antitumor efficacy as compared to other formulations. These studies confirmed that TPPLs are a safe and efficacious treatment for breast cancer.
Topics: Liposomes; Humans; Hydrogen-Ion Concentration; Breast Neoplasms; Female; Receptor, ErbB-2; Paclitaxel; Animals; Mice; Polyethylene Glycols; Drug Liberation; Trastuzumab; Cell Line, Tumor; Drug Screening Assays, Antitumor; Particle Size; Cell Survival; Cell Proliferation; Antineoplastic Agents; Mice, Inbred BALB C
PubMed: 37594466
DOI: 10.1080/08982104.2023.2248505 -
Frontiers in Bioengineering and... 2023The incidence and mortality of cancer are gradually increasing. The highly invasive and metastasis of tumor cells increase the difficulty of diagnosis and treatment, so... (Review)
Review
The incidence and mortality of cancer are gradually increasing. The highly invasive and metastasis of tumor cells increase the difficulty of diagnosis and treatment, so people pay more and more attention to the diagnosis and treatment of cancer. Conventional treatment methods, including surgery, radiotherapy and chemotherapy, are difficult to eliminate tumor cells completely. And the emergence of nanotechnology has boosted the efficiency of tumor diagnosis and therapy. Herein, the research progress of nanotechnology used for tumor diagnosis and treatment is reviewed, and the emerging detection technology and the application of nanodrugs in clinic are summarized and prospected. The first part refers to the application of different nanomaterials for imaging and detection , which includes magnetic resonance imaging, fluorescence imaging, photoacoustic imaging and biomarker detection. The distinctive physical and chemical advantages of nanomaterials can improve the detection sensitivity and accuracy to achieve tumor detection in early stage. The second part is about the nanodrug used in clinic for tumor treatment. Nanomaterials have been widely used as drug carriers, including the albumin paclitaxel, liposome drugs, mRNA-LNP, protein nanocages, micelles, membrane nanocomplexes, microspheres et al., which could improve the drug accumulate in tumor tissue through enhanced permeability and retention effect to kill tumor cells with high efficiency. But there are still some challenges to revolutionize traditional tumor diagnosis and anti-drug resistance based on nanotechnology.
PubMed: 37576984
DOI: 10.3389/fbioe.2023.1249875 -
Biomedicine & Pharmacotherapy =... Sep 2023Doxorubicin (DOX) loaded liposomes have been used and studied in the last decades due to the significant decrease in DOX induced cardiac and systemic toxicity relative...
Doxorubicin (DOX) loaded liposomes have been used and studied in the last decades due to the significant decrease in DOX induced cardiac and systemic toxicity relative to administration of free drug. Therefore, new strategies are sought to improve DOX delivery and antitumor activity, while avoiding side effects. Recently, folate-coated pH-sensitive liposomes (SpHL-Fol) have been studied as a tool to enhance cellular uptake and antitumor activity of paclitaxel and DOX in breast cancer cells expressing folate receptor (FR+). However, the elucidation of folate functionalization relevance in DOX-loaded SpHL (SpHL-DOX-Fol) in different cell types (MDA-MB-231, MCF-7, and A549), as well as, the complete safety evaluation, is necessary. To achieve these objectives, SpHL-DOX-Fol was prepared and characterized as previously described. Antitumor activity and acute toxicity were evaluated in vivo through direct comparison of free DOX verses SpHL-DOX, a well-known formulation to reduce DOX cardiotoxicity. The obtained data are crucial to support future translational research. Liposomes showed long-term stability, suitable for biological use. Cellular uptake, cytotoxicity, and percentage of migration inhibition were significantly higher for MDA-MB-231 (FR+) treated with SpHL-DOX-Fol. In addition, SpHL-DOX-Fol demonstrated a decrease in the systemic toxic effects of DOX, mainly in renal and cardiac parameters evaluation, even using a higher dose (20 mg/kg). Collectively these data build the foundation of support demonstrating that SpHL-DOX-Fol could be considered a promising drug delivery strategy for the treatment of FR+ breast tumors.
Topics: Liposomes; Folic Acid; Doxorubicin; Drug Delivery Systems; Hydrogen-Ion Concentration; Cell Line, Tumor
PubMed: 37541172
DOI: 10.1016/j.biopha.2023.115280